Human pharmacokinetics of XBD173 and etifoxine distinguish their potential for pharmacodynamic effects mediated by translocator protein.

XBD173 and etifoxine are translocator protein (TSPO) ligands that modulate inflammatory responses in preclinical models. Limited human pharmacokinetic data is available for either molecule, and the binding affinity of etifoxine for human TSPO is unknown. To allow for design of human challenge experiments, we derived pharmacokinetic data for orally administered etifoxine (50 mg 3 times daily) and XBD173 (90 mg once daily) and determined the binding affinity of etifoxine for TSPO. For XBD173, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 1.0 nM, which is similar to XBD173 binding affinity. For etifoxine, maximum plasma concentration and free fraction measurements predicted a maximal free concentration of 0.31 nM, substantially lower than the Ki for etifoxine in human brain derived here (7.8 µM, 95% CI 4.5-14.6 µM). We conclude that oral XBD173 dosing at 90 mg once daily will achieve pharmacologically relevant TSPO occupancy. However, the occupancy is too low for TSPO mediated effects after oral dosing of etifoxine at 50 mg 3 times daily.

Risperidone versus placebo for aggression following traumatic brain injury: a feasibility randomised controlled trial.

OBJECTIVES: To conduct a feasibility randomised controlled trial of risperidone for the treatment of aggression in adults with traumatic brain injury (TBI). DESIGN: Multicentre, parallel design, placebo controlled (1:1 ratio) double-blind feasibility trial with an embedded process evaluation. No statistical comparison was performed between the two study groups. SETTING: Four neuropsychiatric and neurology outpatient clinics in London and Kent, UK. PARTICIPANTS: Our aim was to recruit 50 patients with TBI over 18 months. Follow-up participants at 12 weeks using a battery of assessment scales to measure changes in aggressive behaviour and irritability (Modified Overt Aggression Scale (MOAS)-primary outcome, Irritability Questionnaire) as well as global functioning (Glasgow Outcome Scale-Extended, Clinical Global impression) and quality of life (EQ-5D-5L, SF-12), mental health (Hospital Anxiety and Depression Scale) and medication adverse effects (Udvalg for Kliniske Undersøgelser). RESULTS: Six participants were randomised to the active arm of the trial and eight to the placebo arm over a 10-month period (28% of our target). Two participants withdrew because of adverse events. Twelve out of 14 (85.7%) patients completed a follow-up assessment at 12 weeks. At follow-up, the scores of all outcome measures improved in both groups. Placebo group showed numerically better score change according to the primary outcome MOAS. No severe adverse events were reported. The overall rate of adverse events remained low. Data from the process evaluation suggest that existence of specialised TBI follow-up clinics, availability of a dedicated database of TBI patients' clinical details, simple study procedures and regular support to participants would enhance recruitment and retention in the trial. Feedback from participants showed that once in the study, they did not find the trial procedure onerous. CONCLUSIONS: It was not feasible to conduct a successful randomised trial of risperidone versus placebo for post-TBI aggression using the methods we deployed in this study. It is not possible to draw any definitive conclusion about risperidone's efficacy from such a small trial. TRIAL REGISTRATION NUMBER: ISRCTN30191436.

Recognition and treatment of depression in older adults admitted to acute hospitals in England.

Levels of awareness and treatment of depression in older adults admitted to acute hospitals are unclear. This study aims to examine the proportion of older adults diagnosed with depression in acute hospitals, treatment, referral, and communication between secondary and primary healthcare services following discharge. Retrospective examination of records of 766 older adults admitted to 27 acute hospitals in England was carried out. Ninety-eight (12.7%, 95% confidence interval (CI) = 10.6-15.3) records included a diagnosis of depression of which eight (1.0%, 95% CI = 0.5-2.0) had a new diagnosis made during their hospital admission. All newly diagnosed and 76 (84.4%, 95% CI = 75.5-90.5) of those with an existing diagnosis of depression were prescribed antidepressant medication. Six (75.0%, 95% CI = 40.9-92.8) of those with a new diagnosis, and 21 (23.3%, 95% CI = 15.8-33.0) with an existing diagnosis of depression were referred to liaison psychiatry. References to mental health were made in 50 (51.0%, 95% CI = 41.2-60.6) discharge letters sent to primary care. Very few older adults admitted to acute hospitals in this study were diagnosed with depression during their inpatient stay. Opportunities for improving the mental and physical health of such patients appear to be being missed.

Impact of a peer-review network on the quality of inpatient low secure mental health services: cluster randomised control trial.

BACKGROUND: Peer-review networks aim to help services to improve the quality of care they provide, however, there is very little evidence about their impact. We conducted a cluster randomized controlled trial of a peer-review quality network for low-secure mental health services to examine the impact of network membership on the process and outcomes of care over a 12 month period. METHODS: Thirty-eight low secure units were randomly allocated to either the active intervention (participation in the network n = 18) or the control arm (delayed participation in the network n = 20). A total of 75 wards were assessed at baseline and 8 wards dropped out the study before the data collection at 12 month follow up. The primary outcome measure was the quality of the physical environment and facilities of the services. The secondary outcomes included: safety of the ward, patient mental wellbeing and satisfaction with care, staff burnout, training and supervision. We hypothesised that, relative to control wards, the quality of the physical environment and facilities would be higher on wards in the active arm of the trial 12 months after randomization. RESULTS: The difference in the primary outcome between the groups was not statistically significant (4.1; 95% CI [- 0.2, 8.3] p = 0.06). The median number of untoward incidents rose in control services and remained the same at the member of the network (Difference between members and non-members = 0.55; 95% IC [0.29, 1.07] p = 0.08). At follow up, a higher proportion of staff in the active arm of the trial indicated that they felt safe on the ward relative to those in the control services (p = 0.04), despite reporting more physical assaults (p = 0.04). Staff working in services in the active arm of the trial reported higher levels of burnout relative to those in the control group. No difference was seen in patient outcomes. CONCLUSIONS: We did not find evidence that participation in a peer-review network led to marked changes in the quality of the physical environment of low secure mental health services at 12 months. Future research should explore the impact of accreditation schemes and examine longer term outcomes of participation in such networks. TRIAL REGISTRATION: ISRCTN79614916 . Retrospectively registered 28 March 2014.

Aggression Following Traumatic brain injury: Effectiveness of Risperidone (AFTER): study protocol for a feasibility randomised controlled trial.

BACKGROUND: Traumatic brain injury (TBI) is a major public health concern and many people develop long-lasting physical and neuropsychiatric consequences following a TBI. Despite the emphasis on physical rehabilitation, it is the emotional and behavioural consequences that have greater impact on people with TBI and their families. One such problem behaviour is aggression which can be directed towards others, towards property or towards the self. Aggression is reported to be common after TBI (37-71%) and causes major stress for patients and their families. Both drug and non-drug interventions are used to manage this challenging behaviour, but the evidence-base for these interventions is poor and no drugs are currently licensed for the treatment of aggression following TBI. The most commonly used drugs for this purpose are antipsychotics, particularly second-generation drugs such as risperidone. Despite this widespread use, randomised controlled trials (RCTs) of antipsychotic drugs, including risperidone, have not been conducted. We have, therefore, set out to test the feasibility of conducting an RCT of this drug for people who have aggressive behaviour following TBI. METHODS/DESIGN: We will examine the feasibility of conducting a placebo-controlled, double-blind RCT of risperidone for the management of aggression in adults with TBI and also assess participants' views about their experience of taking part in the study. We will randomise 50 TBI patients from secondary care services in four centres in London and Kent to up to 4 mg of risperidone orally or an inert placebo and follow them up 12 weeks later. Participants will be randomised to active or control treatment in a 1:1 ratio via an external and remote web-based randomisation service. Participants will be assessed at baseline and 12-week follow-up using a battery of assessment scales to measure changes in aggressive behaviour (MOAS, IRQ) as well as global functioning (GOS-E, CGI), quality of life (EQ-5D-5L, SF-12) and mental health (HADS). We will also assess the adverse effect profile with a standard scale (UKU) and collect available data from medical records on blood tests (serum glucose/HbA1c, lipid profile, prolactin), and check body weight and blood pressure. In addition completion of the MOAS and a check for any new or worsening side-effect will be completed weekly and used by the prescribing clinician to determine continuing dosage. Family carers' wellbeing will be assessed with CWSQ. Service use will be recorded using CSRI. A process evaluation will be carried out at the end of the trial using both qualitative and quantitative methodology. DISCUSSION: Aggressive behaviour causes immense distress among some people with TBI and their families. By examining the feasibility of a double-blind, placebo-controlled RCT, we aim to discover whether this approach can successfully be used to test the effects of risperidone for the treatment of aggressive behaviour among people with aggression following TBI and improve the evidence base for the treatment of these symptoms. Our criteria for demonstrating success of the feasibility study are: (1) recruitment of at least 80% of the study sample, (2) uptake of intervention by at least 80% of participants in the active arm of the trial and (3) completion of follow-up interviews at 12 weeks by at least 75% of the study participants. TRIAL REGISTRATION: ISRCTN30191436 . Registered on 19 December 2016.

Impact of peer-led quality improvement networks on quality of inpatient mental health care: study protocol for a cluster randomized controlled trial.

BACKGROUND: Quality improvement networks are peer-led programmes in which members of the network assess the quality of care colleagues provide according to agreed standards of practice. These networks aim to help members identify areas of service provision that could be improved and share good practice. Despite the widespread use of peer-led quality improvement networks, there is very little information about their impact. We are conducting a cluster randomized controlled trial of a quality improvement network for low-secure mental health wards to examine the impact of membership on the process and outcomes of care over a 12 month period. METHODS: Standalone low secure units in England and Wales that expressed an interest in joining the quality improvement network were recruited for the study from 2012 to 2014. Thirty-eight units were randomly allocated to either the active intervention (participation in the network n = 18) or a control arm (delayed participation in the network n = 20). Using a 5 % significance level and 90 % power, it was calculated that a sample size of 60 wards was required taking into account a 10 % drop out. A total of 75 wards were assessed at baseline and 8 wards dropped out the study before the data collection at follow up. Researchers masked to the allocation status of the units assessed all study outcomes at baseline and follow-up 12 months later. The primary outcome is the quality of the physical environment and facilities on the wards. The secondary outcomes are: safety of the ward, patient-rated satisfaction with care and mental well-being, staff burnout, training and supervision. Relative to control wards, it is hypothesized that the quality of the physical environment and facilities will be higher on wards in the active arm of the trial 12 months after randomization. DISCUSSION: To our knowledge, this is the first randomized evaluation of a peer-led quality improvement network that has examined the impact of participation on both patient-level and service-level outcomes. The study has the potential to help shape future efforts to improve the quality of inpatient care. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79614916 . Retrospectively registered 28 March 2014].

Efficacy and feasibility of home-based training for individuals with homonymous visual field defects.

BACKGROUND: Homonymous visual field defects (HVFDs) are one of the most common consequences of stroke. Compensatory training encourages affected individuals to develop more efficient eye movements to improve function. However, training is typically supervised, which can be time consuming and costly. OBJECTIVE: To develop and evaluate the efficacy and feasibility of an unsupervised reading and exploration computer training for individuals with HVFDs. METHODS: Seventy individuals with chronic HVFDs were randomly assigned to 1 of 2 groups: intervention or control. The former received 35 hours of reading and exploration training, and the latter received 35 hours of control training. Visual and attentional abilities were assessed before and after training using perimetry, visual search, reading, activities of daily living, the Test of Everyday Attention, and a Sustained Attention to Response task. RESULTS: Eighteen individuals failed to complete the training; analyses were conducted on the remaining 28 intervention and 24 control group participants. Individuals in the intervention group demonstrated significant improvements in the primary outcomes of exploration (12.87%, 95% confidence interval [CI] = 8.44% to 17.30%) and reading (18.45%, 95% CI = 9.93% to 26.97%), which were significantly greater than those observed following the control intervention (exploration = 4.80%, 95% CI = 0.09% to 9.51%; reading = 1.95%, 95% CI = -4.78% to 8.68%). Participants in the intervention group also reported secondary subjective improvements, although these were not matched by objective gains in tasks simulating activities of daily living. CONCLUSIONS: Home-based compensatory training is an inexpensive accessible rehabilitation option for individuals with HVFDs, which can result in objective benefits in searching and reading, as well as improving quality of life.

Task- and response related dissociations between neglect in near and far space: a morphometric case study.

INTRODUCTION: Patients with unilateral neglect may show line bisection errors selectively in either near (within hand reaching) or far (beyond hand reaching) space which suggests that these two spatial areas are coded differently by the brain. This exploratory study investigated, whether any difference in performance between these spatial domains might be task-independent or modulated by the requirement for a motor response. METHODS: A 31-year-old right brain damaged patient (MF) and a group of age matched healthy controls were assessed with two serial visual search tasks and a Landmark paradigm. Both types of task required either a directional (pointing) or non-directional (button press) motor response. Participants were assessed with both task types and response modes in near (57 cm) and far space (114 cm). RESULTS: MF showed left neglect during visual search only in far space for the perceptual condition and in near space for the motor condition. MF showed no neglect in both versions of the Landmark task irrespective of spatial distance. A voxel-based morphometric assessment of MF's brain lesion showed marked damage in the right ventro-temporal cortex, superior temporal gyrus, insula, inferior frontal gyrus, angular gyrus and bilaterally in the posterior cingulate cortex. CONCLUSIONS: Our preliminary findings suggest that processing of far space during visual search is associated with ventral stream damage but only when space is coded through visual information. Neglect involving directional motor activity in near space seems to be associated with damage of structures sharing close connections with the dorsal stream.

Pathways involved in human conscious vision contribute to obstacle-avoidance behaviour.

Human patients with visual field defects following damage to their primary visual cortex (V1) will often misperceive the midpoint of a horizontal line. They tend to shift the midpoint away from the real position towards their blind field. In patients with unilateral neglect, where midpoint shifts can also be observed, these perceptual errors do not lead to errors in an obstacle-avoidance task, which also requires the ability to find the midpoint between two obstacles. This dissociation in neglect patients was taken as evidence that obstacle-avoidance performance is guided by visual information from the dorsal visual stream. Recently it was shown that a patient with hemianopia could avoid an obstacle presented in his blind field. This suggests that obstacle-avoidance behaviour can be guided by subconscious vision alone involving a direct route from extrageniculate structures in the brain to dorsal stream areas. To investigate whether obstacle avoidance relies only on this subconscious route or also uses information from pathways involved in conscious vision, we examined the effect of the hemianopic shift on obstacle-avoidance behaviour. This shift is found in tasks where a conscious visual judgement is required and presumably arises in pathways underlying conscious vision (V1 and ventral stream areas). We compared the performance of six patients with left hemianopia with the performance of six patients with right hemianopia. We found a clear bias in both groups, which also affected obstacle-avoidance performance. It is thus concluded that obstacle avoidance does not bypass the system for conscious vision completely.

Near and far space neglect: task sensitivity and anatomical substrates.

Most group studies which have investigated neglect for near and far space have found an increased severity of symptoms in far space compared to near space. However, the majority of these studies used relatively small samples and based their findings almost exclusively on line bisection performance. The aim of the present study was, therefore, to explore the occurrence of neglect for near and far space in a larger group of unselected right brain damaged patients and to evaluate whether neglect specific to near and far space is a task-related deficit or generalises across distance irrespective of task. In addition, a lesion overlap analysis was carried out to identify critical lesion sites associated with distance specific neglect deficits. Thirty-eight right hemisphere damaged patients carried out a line bisection and a cancellation task by using a pen in near space (40 cm) and a laser pointer in far space (320 cm). The results showed that both the number of left-sided omissions and rightward bisection errors were significantly increased in near compared to far space. Distance specific dissociations, albeit less common, were more frequently observed for cancellation than line bisection. These results suggest that space representation in neglect is more severely impaired in near than in far space. In addition, distance related dissociations in neglect may depend on task demands. Although the anatomical findings were broadly consistent with a dorsal and ventral stream dichotomy for near and far space processing, they also suggest the involvement of intermediate structures in distance related neglect phenomena.

Visuomotor adaptation is impaired in patients with unilateral neglect.

Patients with unilateral neglect tend to ignore sensory information from their contralesional hemispace. Many symptoms of neglect can be reduced by exposing patients to rightward-shifting prism goggles. It was noted that the effects on neglect symptoms last for at least two hours. This seems surprising in light of the fact that the after-effect of prism adaptation in healthy subjects lasts only for a few trials. To account for this discrepancy Michel et al. (2003) referred to anecdotal observations which suggested that neglect patients show little awareness of prism-induced spatial errors. They argued that this lack of awareness might interfere with more conscious attempts to compensate for the prism goggles (called strategic control) and thereby enhance the effects of more implicit corrective mechanisms (called spatial realignment) leading to more pronounced and longer-lasting after-effects. We examined this hypothesis in a group of neglect patients, patients with right-hemispheric lesions but no neglect and a group of healthy age-matched controls. Our findings confirm that strategic control mechanisms are impaired in neglect patients. However, their after-effects seem neither reduced nor pathologically increased, thereby suggesting that the two mechanisms of prism adaptation, namely strategic control and spatial realignment are quite independent of each other. Furthermore we found that these deficits are quite specific for neglect since other patients with right-hemisphere lesions but no neglect are not impaired in this task. We discuss the implications of our findings for our understanding of visual neglect, prism adaptation and the perception and action model.

Sustained attention in traumatic brain injury (TBI) and healthy controls: enhanced sensitivity with dual-task load.

Poor sustained attention or alertness is a common consequence of traumatic brain injury (TBI) and has a considerable impact on the recovery and adjustment of TBI patients. Here, we describe the development of a sensitive laboratory task in healthy subjects (Experiment 1) and its enhanced sensitivity to sustained attention errors in TBI patients (Experiment 2). The task involves withholding a key press to an infrequent no-go target embedded within a predictable sequence of numbers (primary goal) and detecting grey-coloured targets within the sequence (secondary goal). In Experiment 1, we report that neurologically healthy subjects are more likely to experience a lapse of attention and neglect the primary task goal, despite ceiling performance on the secondary task. Further, attentional lapses on the task correlated with everyday attentional failures and variability of response time. In Experiment 2, the task discriminates between TBI patients and controls with a large effect size. The dual-task yields more errors in both groups than a simple task involving only the primary goal that is commonly used to detect sustained attention deficits in neurologically impaired groups. TBI patients' errors also correlated with everyday cognitive failures and variability of response time. This was not the case in the simple version of the task. We conclude that the dual-task demand associated with this task enhances its sensitivity as a measure of sustained attention in TBI patients and neurologically healthy controls that relates to everyday slips of attention.

Attenuation of spatial attentional asymmetries with poor sustained attention.

The co-existence of deficits in sustained and spatial attention in patients with acquired damage to the right cerebral hemisphere has led to the proposition that sustained attention could be a marker for left spatial inattention, or neglect. We investigated the possibility that reductions in leftward spatial attentional asymmetries could arise from individual differences in the capacity for sustained attention even within healthy adult populations. We observed that healthy participants who performed poorly on a test of sustained attention had a significantly attenuated left spatial bias, relative to those with good sustained attention capacity, on a free-viewing spatial attention test. Our results provide further support for the notion that sustained attention may exert a modulatory influence on spatial attention.